17-40354320-C-G

Variant names:

• chr17-40354320-C-G
• rs786205678
• NM_000964.4:c.826C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_000964.4(RARA):​c.826C>G​(p.Arg276Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R276Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RARA NM_000964.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.609
• Publications: 0 publications found

Genes affected

RARA (HGNC:9864): (retinoic acid receptor alpha) This gene represents a nuclear retinoic acid receptor. The encoded protein, retinoic acid receptor alpha, regulates transcription in a ligand-dependent manner. This gene has been implicated in regulation of development, differentiation, apoptosis, granulopoeisis, and transcription of clock genes. Translocations between this locus and several other loci have been associated with acute promyelocytic leukemia. Alternatively spliced transcript variants have been found for this locus.[provided by RefSeq, Sep 2010]

RARA Gene-Disease associations (from GenCC):

• multiple congenital anomalies/dysmorphic syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• acute promyelocytic leukemia

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-40354321-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 985591.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARA	NM_000964.4	c.826C>G	p.Arg276Gly	missense_variant	Exon 7 of 9	ENST00000254066.10	NP_000955.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RARA	ENST00000254066.10	c.826C>G	p.Arg276Gly	missense_variant	Exon 7 of 9	1	NM_000964.4	ENSP00000254066.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	24
DANN	Benign	0.91
DEOGEN2	Uncertain	0.75	D;D;.;D;.;.
Eigen	Benign	-0.029
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.46	N
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M;M;.;.;.;.
PhyloP100		-0.61
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.2	D;D;D;D;D;.
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;D;D;D;.
Sift4G	Uncertain	0.0060	D;D;D;D;D;D
Polyphen		0.91	P;P;.;.;.;.
Vest4		0.95
MutPred		0.88		Loss of stability (P = 0.0693);Loss of stability (P = 0.0693);.;.;.;.;
MVP		1.0
MPC		2.3
ClinPred		0.98	D
GERP RS		0.18
Varity_R		0.96
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs786205678; hg19: chr17-38510572;